The essence of malignancy is the ability of a tumor to spread and overwhelm its host in spite of its own initial sensitivity to radio-\and chemotherapy, and in spite of what often appears to be a sensitive and adequate host immune defense system. Natural killer (NK) cells are naturally occurring lymphoid cells which are spontaneously cytotoxic in vitro to a variety of cultured tumor cell lines, and recent evidence suggests that NK cells may play a major role in immunological defenses against developing cancers. Because NK cells have significant lytic potential, it would seem probable that their activities would be closely regulated in vivo. Insights into how NK cells are regulated in vitro may be crucial to understanding why NK cell activities may not be effective against certain types of tumors in vivo, thus leading to significant improvements in future approaches to clinical immunotherapy. We are investigating mechanisms whereby human NK cells are regulated in vitro by: (1) interactions with other cellular elements derived from human peripheral blood; and by (2) "responses" of tumor target cells themselves to the presence and cytolytic activities of the NK cells. Both of these aspects are being studied in a 4-hour 51-chromium-release assay which uses the K562 erythroleukemia cell line as tumor target cells. We have already found that blood granulocytes are potent inhibitors of in vitro NK cell function and are investigating granulocyte effects on soluble natural killer cytotoxic factors (NKCF). Further, expression of class II antigens (HLA-DR or "Ia-like") by potential target cell seems to protect them from cytotoxic attack. Similar mechanism(s) of regulation of antibody-dependent cell-mediated cytotoxicity (ADCC) are being investigated.